Reviewing the RCC Treatment Algorithm and Novel Trial Regimens

RCC Treatment Algorithm for Early or Metastatic Disease

On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Katy Beckermann, MD, PhD, of Tennessee Oncology, to discuss the treatment algorithms for early and advanced RCC, as well as recent data that may expand the available standard of care treatment options.

Treatment Algorithm for Early RCC

For patients with localized RCC, the standard of care is partial or radical nephrectomy. In addition, the FDA approved adjuvant therapy with pembrolizumab for patients with intermediate-high or high risk of recurrence after surgery on November 17, 2021, based on the KEYNOTE-564 trial. Given the potential for curative outcomes with nephrectomy alone, there is debate on whether some patients would be overtreated with pembrolizumab.

In Dr. Beckermann’s practice, she considers adjuvant pembrolizumab for all patients who meet the KEYNOTE-564 inclusion criteria, but more strongly prefers it for patients with the highest-risk features, such as M1 disease or sarcomatoid differentiation. In the current RCC treatment algorithm, use of adjuvant pembrolizumab should be a shared decision with the patient. Future studies will hopefully identify biomarkers that can guide patient selection and avoid overtreatment, said Dr. Beckermann.

Potential to Improve Adjuvant Therapy Efficacy

Recent data from the LITESPARK-022 trial suggest there is potential to intensify adjuvant pembrolizumab by combining it with belzutifan. Compared with adjuvant pembrolizumab alone, adjuvant pembrolizumab plus belzutifan improved DFS outcomes, according to a presentation from the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. 

The DFS benefit with belzutifan was meaningful, but it’s difficult to broadly implement intensified adjuvant therapy in this patient population, given that adjuvant pembrolizumab alone is debatable and belzutifan adds notable toxicities, such as anemia and hypoxia, said Dr. Beckermann. If this combination is approved, utilization will require even more careful patient selection plus additional monitoring and supportive care to address toxicities. 

Frontline Metastatic RCC Treatment Algorithm

Approved frontline treatment options for advanced or metastatic RCC include dual immunotherapy and immunotherapy plus tyrosine kinase inhibitor (TKI) doublets such as avelumab plus axitinib, nivolumab plus ipilimumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and pembrolizumab plus lenvatinib. Notably, the treatment algorithm for metastatic RCC can differ for patients with recurrent or progressive disease after adjuvant treatment versus those with de novo metastatic disease.

For patients with recurrent or progressive disease and prior adjuvant immunotherapy, the viability of rechallenging with immunotherapy combinations is an open question. Ongoing studies are generating data to answer this question, but current treatment decisions may be based on duration since prior therapy. If patients progress during cycles of adjuvant immunotherapy, that may support switching to another mechanism. Conversely, if patients recur some amount of time after stopping systemic therapy, it may be appropriate to rechallenge with immunotherapy combinations, said Dr. Beckermann. 

For patients with de novo metastatic RCC, selecting a frontline treatment regimen should be an individualized choice based on patients’ disease characteristics. If patients have aggressive features and may not reach additional lines of therapy, immunotherapy plus TKI combinations may be preferred for their rapid responses. In contrast, dual immunotherapy combinations may achieve more durable responses in patients who can remain on therapy longer. When choosing between TKI–based regimens, oncologists should balance the different side effect profiles of each TKI with individual patients’ comorbidities, Dr. Beckermann said.

Refractory or Relapsed Metastatic RCC Treatment Options

Approved treatment options for RCC in the second-line and beyond include nivolumab for immunotherapy–naïve patients, lenvatinib plus everolimus, and single-agent TKIs. More recently, the LITESPARK-011 trial showed that lenvatinib plus belzutifan improved response rate and progression-free survival, and approximately doubled the duration of response compared with single-agent cabozantinib. These data are more immediately practice-changing than those for belzutifan in the adjuvant setting, but toxicities associated with belzutifan remain a limiting factor. Once approved, the LITESPARK-011 regimen may be an especially reasonable sequencing option after frontline treatment with nivolumab plus ipilimumab or nivolumab plus cabozantinib, said Dr. Beckermann.